Mycosis includes superficial mycosis represented by various trichophytoses, cutaneous candidiasis, tinea versicolor and the like, and deep mycosis represented by fungal meningitis, fungal respiratory infection, fungemia, mycosis of urinary tract and the like.
Superficial mycosis is a mycosis wherein epidermis, hair, nail and the like are infected with fungi, and trichophytosis caused by fungi of the genus Trichophyton as the major causative microorganism accounts for about 90% of the whole, and candidiasis and tinea versicolor account for the remaining 10%. The number of domestic patients with trichophytosis is estimated to be 21 million for tinea pedis and 12 million for tinea unguium.
Tinea unguium is a refractory disease, and oral antifungal agents such as terbinafine, itraconazole and the like are generally used for the treatment. Since the treatment requires oral administration of the medicament for at least 3 months, medication adherence of the patients is low. In addition, insufficient eradication effect against fungi at the site of infection also poses problems of recurrence and relapse after the treatment. Furthermore, drug-drug interaction, and side effects such as hepatopathy, gastrointestinal disorder and the like also pose problems, and the treatment is sometimes restricted in elderly people and patients with complication or pre-existing disease.
Therefore, an antifungal agent highly effective against tinea unguium by topical application free from systemic side effects and drug interaction is demanded. To exhibit effects by topical administration, the medicament is required to sufficiently penetrate into the thick horny layers of the nail plate and show an antifungal activity against Trichophyton fungi in the nail and nail bed.
As an external preparation for the treatment of tinea unguium, a nail lacquer preparation of amorolfine has already been applied clinically overseas. While amorolfine shows a superior anti-Trichophyton activity, it shows low penetrability into the nail, and its clinical effect is not sufficient.
As a biaryl derivative, the following compound is known. Patent Document 1 describes a compound represented by the formula:
wherein each symbol is as defined is Patent Document 1 as a compound having an inhibitory activity against kinases such as Tie-2 and the like.
Patent Document 2 describes a compound represented by the formula:
wherein each symbol is as defined in Patent Document 2, as a compound having an inhibitory activity against protein kinases such as Tie-2 and the like.
Patent Document 3 describes a compound represented by the formula:
wherein each symbol is as defined in Patent Document 3, as a compound having an Aurora kinase inhibitory activity.
Patent Document 4 describes a compound represented by the formula:
wherein each symbol is as defined in Patent Document 4, as a compound having an inhibitory activity against protein kinases such as Tie-2 and the like.
It is disclosed that the above-mentioned compounds are useful for the treatment of angiogenesis and cancer by inhibiting various kinases.
On the other hand, Patent Document 5 describes a compound represented by the formula:
wherein each symbol is as defined in Patent Document 5, as a compound having a phosphodiesterase 10 inhibitory activity.
Patent Document 6 describes a compound represented by the formula:
wherein each symbol is as defined in Patent Document 6, as a compound having a phosphodiesterase 10 inhibitory activity.
It is disclosed that these above-mentioned compounds are useful for the treatment of obesity, non-insulin-dependent diabetes mellitus, schizophrenia, bipolar disorder, obsessive-compulsive disorder and the like by inhibiting phosphodiesterase 10.
However, these prior art documents do not specifically disclose the compound of the formula (I) of the present invention, and do not describe or suggest that the compound has an anti-Trichophyton activity, and is useful for the treatment of diseases caused by Trichophyton fungi.